N-acetyl-S-famesyl-L-cysteine (AFC) and its derivatives (isoprenylcysteine (IPC) analogs) represent a novel class of topically absorbed NSAIDs whose activity is restricted to the site of application with no detectable systemic effects and no adverse affects such as skin atrophy or inhibition of wound healing. In a double- blinded, vehicle-controlled cosmetic human use study;AFC was shown to inhibit chronic skin erythema. Based on our previous work we hypothesize we can identify more potent and selective 2nd generation IPC compounds to effectively treat chronic inflammatory skin diseases associated with erythema. If it is determined that IPC analogs inhibit cytokine release induced by inflammatory or other mediators, reduce skin erythema more potently than AFC and a predictive relationship is established between in vitro and in vivo activity for IPC analogs, the feasibility of the project will have been demonstrated. Prof. Richard D. Granstein, Chairman of the Department of Dermatology at the Weill Medical College of Cornell University, and Dr. John Seykora, assistant Professor of the Department of Dermatology at the University of Pennsylvania, will contribute to this effort to successfully complete the Aims of this grant. This will lead in Phase II to a program to identify and develop novel pharmaceutical leads for the treatment of inflammatory skin diseases associated with erythema such as eczema (e.g. atopic dermatitis, seborrheic dermatitis) and rosacea. PUBLIC HEALTH RELEVANCE: Treatment for chronic inflammatory skin diseases characterized by a prominent degree of erythema, remains largely unsatisfactory and the development of more effective therapies represents a great unmet medical need. The paucity of relevant experimental models for these diseases hinder drug development efforts;thus, new treatments and screening methods to test for efficacy are required. Successful development of this novel class of topical non-steroidal anti-inflammatories will provide an important additional, and potentially better, therapeutic option for people suffering from rosacea and eczema (e.g. atopic dermatitis, seborrheic dermatitis).